Children infected with HIV display great variability in their clinical course and rate of progression to AIDS. The reasons for this variability are not known. Increasing evidence from adult studies suggests that the cellular immune response is a critical determinant of viral containment, and likely accounts for much of the observed variability in clinical progression. Detailed studies of the HIV-specific immune responses generated by adults with long-term nonprogressive infection have revealed elements of the host immune response that appear to be essential for effective viral control. Much less is known about the specific immune responses generated by children with HIV infection. Recently, sensitive new techniques have enabled the detailed assessment of virus-specific immune responses using very few lymphocytes. The candidate has adapted these techniques for the analysis of pediatric samples. The proposed investigations will include a comprehensive characterization of HIV-specific cytotoxic T-lymphocyte and T- helper responses in children who are able to control HIV at very low levels in the absence of potent antiretroviral therapy. The magnitude, breadth, and epitope specificity of these responses will be assessed and compared to those of age-matched control subjects. This unique cohort will then be followed longitudinally, in order to gain a better understanding of the immunologic events surrounding the loss of viral control. In particular, the contribution of viral escape mutants within targeted CTL and/or T-helper epitopes to clinical progression will be determined. Identification of the precise correlates of viral containment in children will provide important insights into the pathogenesis of vertical infection, and will greatly assist the rational design of HIV vaccines and immunotherapies. The candidate will seek balanced multidisciplinary training toward the goal of becoming an independent clinical investigator with both scientific expertise in HIV immunity in children and the clinical research skills needed to translate this research into novel therapies for HIV-infected children. This research will be conducted under the guidance of leading investigators in the field of HIV immunopathogenesis in adults.